Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology

Silva, B. M.; Veras, F. P.; Gomes, G.; Cambier, S.; Silva, G.; Quadros, A.; Caetite, D.; Nascimento, D.; Silva, C.; Silva, J.; Damasceno, S.; Schneider, A.; Beretta, F.; Batah, S.; Castro, I.; Paiva, I.; Rodrigues, T.; Salina, A. C. G.; Martins, R.; Cebinelli, G.; Bibo, N.; Jorge, D.; Nakaya, H. I.; Zamboni, D. S.; Leiria, L.; Fabro, A.; Alves-Filho, J. C.; Arruda, E.; Louzada-Junior, P.; Oliveira, R.; Cunha, L. D.; Van-Mol, P.; Vanderbeke, L.; Feys, S.; Wauters, E.; Brandolini, L.; Cunha, F.; Kohl, J.; Allegretti, M.; Lambrechts, D.; Wauters, J.; Proost, P.; Cunha, T. M.

doi:10.1101/2022.07.03.498624

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bioRxiv · 10.1101/2022.07.03.498624

Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology

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Abstract

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.

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Silva, B. M., Veras, F. P., Gomes, G., Cambier, S., Silva, G., Quadros, A., Caetite, D., Nascimento, D., Silva, C., Silva, J., Damasceno, S., Schneider, A., Beretta, F., Batah, S., Castro, I., Paiva, I., Rodrigues, T., Salina, A. C. G., Martins, R., Cebinelli, G., Bibo, N., Jorge, D., Nakaya, H. I., Zamboni, D. S., Leiria, L., Fabro, A., Alves-Filho, J. C., Arruda, E., Louzada-Junior, P., Oliveira, R., Cunha, L. D., Van-Mol, P., Vanderbeke, L., Feys, S., Wauters, E., Brandolini, L., Cunha, F., Kohl, J., Allegretti, M., Lambrechts, D., Wauters, J., Proost, P., Cunha, T. M.. 2022-07-05. Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology. https://doi.org/10.1101/2022.07.03.498624

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